The goal of this project is to utilize high throughput genomic methodologies to identify genes contributing to tumorigenesis and other tumor phenotypes in a mouse melanoma model system. The rationale for this approach is that the process of tumorigenesis as well as subsequent tumor phenotypes are the consequence of a series of genetic changes which functionally distinguish the tumor cell from the normal cell. The Specific Aims of this program are as follows: 1) To implement a program of gene discovery for the identification and subsequent characterization of genes which contribute to melanoma tumorigenesis in the mouse Ink4a -/- tyrRas model system through the simultaneous application of high definition LOH studies and transcriptional profiling studies on a large set of tumors produced on a FVB/N X 129 F1 genetic background; 2) To develop and validate novel genomic technologies for the analysis of sites of DNA methylation and transcription factor binding and apply these approaches to the genetic analysis of melanoma tumorigenesis in the Ink4a-/- tyrRas mouse model; 3) To map and subsequently identify modifier genes that control tumorigenesis in the mouse Ink4a -/- tyrRas model system; 4) To apply LOH analysis, genetic modifier mapping and other gene identification methodologies developed to the analysis of treatment response and metastasis in the mouse Ink4a -/- tyrRas model system and its derivatives; 5) To evaluate the significance of genes discovered in the mouse model to human cancer DNA sequence analysis of human tumor DNA to identify mutations in tumors in the human gene homologous to the mouse gene which we discover.